Dialkylaminoethyl piperazinepropionates and process



United States Patent Ofihce v 3,015,659 DIALKYLAMINOETHYL PIPERAZINEPROPIO- NATES AND PROCESS- Kurt J. Rorig, Glenvi'ew, Ill., assignor to G. D. Searle & Co.', Chicago, Ill.,- a corporation of Delaware .NoDrawing. Filed Apr. 8,1960, Ser. N0. 20,830

7 Claims. (Cl.'260"268)- This invention relates to dialkylaminoalkyl piperazinealkanoates and a process for' the manufacture thereof. More particularly, this invention relates to chemical compounds of the formula respectively, n in the'latter two formulas being defined as before.

Equivalent to the foregoing basic esters for the purposes of this invention are the corresponding acid addition salts of the formula wherein R and Z have the meanings previously assigned; Q represents one equivalent of an anion-for example, chloride, bromide, iodide, nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate, toluenesulfonate, acetate, lactate, succinate, rnalate, maleate, tartrate, citrate, gluconate, ascorbate, -benzoate, cinnamate, or the likewhich, in combination with the cationic portion of a salt aforesaid, is neither pharmacologically nor otherwise undesirable in physiological dosage; and x represents a positive integer amounting to less than 4.

The compounds to which this invention relates are useful because of their valuable pharmacological properties. Thus, for example, they depress the central nervous system; they are anti-fungal agents representa-tively effective 1 inorganic andstrong organic acids, the anionic portions trihydrochl'oride.A solution of 100 parts of N-rn'ethyl-v boiling point under reflux for 9 hours.

against Trichophyton mentagrophytes; and they inhibit the heat, swelling, and redness characteristic of the inflammatory response to tissue injury.

Manufacture of the subject compounds proceeds by heating a selected piperazine of the formula with a di(lower alkyl)aminoethyl acrylate I in an inert solvent, such as butanone, Z and R in the latter two formulas remaining as before. Conversion of the basic esters so produced to acid addition salts is accomplished by admixture with 1, 2, or 3 equivalents of of whicl'i conform to Q as hereinabo-ve set forth. 7

The following examplesdescribe in detail compounds illustrative to thepresent invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be .practiced without departing from the purpose and intent of this disclosure. Throughout" the examples hereinafter set forth, temperatures are given in degrees ,centigrade and relative amounts of materials in parts by weight, except asothei'wise noted. r t E m Z-die'thylaminoelhyl 4-n'1ethyl -;J piperazinepropionate piperazine-and 171 parts of Z-diethylaminoet-hyl acrylate in 2500 parts of butanone is heated at the boiling'pointunder reflux for 9 hours. The resultant solution is diluted with 2000 parts of anhydrous ether and then made barely acid with a solution of hydrogen chloride'in absolute 2- propanol. Upon standing, 2-diethylaminoethyl 4-rnethyll-piperazinepropionate trihydrochloride precipitates as a white crystalline solid which, recrystallized from methanol, melts at 235-237 with decomposition. The product has the formula 1 Example 2 Z-dimethylaminoethyl 4-ethyl-1-piperazinepropi0nate. A solution of 114 parts of N-ethylpiperazine and 143 parts of 2-dimethylaminoethyl acrylate in 2500 parts of b-utanone is heated at the boiling point underrefiux for 9 hours. Solvent is removed by distillation in vacuo, affording 2-dimethyla-minoethyl 4-ethyl-l-piperazinepropionate as the residue, a golden oil. The product has the formula Example 3 Z-diethylaminoethyl 4-(2-hydroxyethyl)-1-piperazinepropiorzate trihydrochloride.-A solution of parts of l-piperazineethanol and '171 ,parts of Z-diethylaminoethyl acrylate in 2500 parts of butanone is heated at the tion of just sufiicient hydrogen chloride dissolved in absolute 2-propanol to induce acidity, solid Z-diethylaminoethyl 4-(2-hydroxyethyl)-1-piperazinepropionate trihydrochloride is precipitated. The product, recovered on a filter and recrystallized from ethanol, melts at approximaltely 230-231 with decomposition. It has the formu a Example 4 Z-dimethylaminoerhyl azinepropionate.-A solution of 144 parts of l-piperazineprop'anol and 143' parts of Z-dimethylarninoethyl acrylate in 2500 parts of butanone is heated at the boiling point under reflux for 8 hours. Removal of solvent by vacuum distillation leaves as the residue, Z-dimethylaminoethyl 4-(3-hydroxypropyl)-1-piperazinepropionte, an oil. The product has'the formula Patented Jan. 2, 1962 Upon introduc- Example 5 Z-dietlzylaminoethyl 4-eth0xycarb0nyl-1-piperazinepr0- pionate dihydrochl0ride.Substitution of 158 parts of N-ethoxycarbonylpiperazine for the l-piperazineethanol called for in Example 3 afiords, by the procedure there detailed, Z-diethylaminoethyl 4-ethoXycarbony1-1-piperaazinepropionate dihydrochloride asa colorless crystalline solid melting at approximately 2282-29 (with decomposition) after recrystallization from ethanol. The product has the formula Example 6 V What is claimed is: l. A compound of the formula 7 4 wherein R represents a lower alkyl radical and Z represents a member of the group consisting of lower alkyl, hydroxy-(lower alkyl), ethoxycarbonyl, and phenyl radicals.

2. A compound of the formula R2NCHzCHzO-%CII2CHN N-R' wherein R and R represent lower alkyl radicals.

3 2-diethylaminoethy1 4-rnethyl-1-piperazineprionate. 4. A compound'of the formula wherein R represents a lower alkyl radical and R" represents a hydroixyflower alkyl) radical.

5. Z-diethylaminoethyl 4 (2 hydroxyethyD-l-piperazinepropionate. i

6. 2-diethylarninoethyl 4-ethoxycarbonyl-l-piperazinepropionate.

nate.

References Citedin the file of this patent UNITED STATES PATENTS 2,617,803 Turner Nov. 11, 1952 OTHER REFERENCES Pollard et al.: Jour. Amer. Chem Soc., vol. 75, pages 2989-2990 (1953).

7; 2-diethylaminoethyl 4 phenyl-l-piperazinepropio- 

1. A COMPOUND OF THE FORMULA 